The side effects of chemotherapeutic agents used in the treatment of malignancy and other indications are well known. Among these side effects are alterations in the levels of various blood cells, including neutrophils, platelets and lymphocytes. The results of these effects can be neutropenia, thrombocytopenia and immune suppression generally. These side effects are not only unpleasant, but they also restrict the efficacy of cancer therapy and place the subject at serious risk of infection and uncontrolled bleeding.
At the present time, there appears to be little practical remediation for these effects. Some approaches are merely palliative, such as supportive care. Others have their own side effects, such as large doses of antibiotics. Still others are expensive and invasive such as transfusions. Still another approach, the administration of growth factors, such as granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), and more newly developed factors such as megakaryocyte growth and development factor (MGDF) and thrombopoietin (TPO) are costly and must be administered by injection. They also have their own associated negative side effects.
Clearly there is a need for a simpler approach, for example a small molecule drug, preferably administerable by mouth, that can protect and restore bone marrow and also stimulate the production of neutrophils, platelets and lymphocytes both in conjunction with chemotherapeutic protocols and in response to other factors which result in hematopoietic suppression such as cyclic and idiopathic neutropenias, thrombocytopenia, and the effects of allograft transplants.
The problems related to current approaches for managing the side effects of chemotherapy and otherwise dealing with suppression of hematopoiesis are solved at least in part by the biological activity of certain simple tripeptide compounds which are inhibitors of the various isoenzymes of glutathione S-transferase.
PCT application WO95/08563 published Mar. 30, 1995, and based on PCT/US94/10797, from which the parent application herein claims priority, discloses these tripeptide compounds which are analogs of glutathione. They are generally inhibitors of glutathione S-transferase activity and the various compounds contained in this group show diverse specificities with respect to glutathione S-transferase isoenzymes.
A subset of these analogs, which is of the general formula ##STR2## and the amides and esters thereof, wherein YCO is .gamma.-glu or .beta.-asp; G* is phenylglycine or glycine; Z is CH.sub.2, O or S; and X is a hydrocarbon radical of 1-20C, have now been found to have the ability to modulate hematopoiesis in bone marrow and in peripheral blood and therefore exert protective effects when chemotherapeutic agents destructive to the hematopoietic system are administered. These compounds also potentiate the desired effects of chemotherapeutic agents. This same subset of glutathione analogs shows inhibition of the .pi. class of glutathione S-transferase (GST), and, in some cases, other classes as well.